The Impact of N-terminal Acetylation of α-Synuclein on Phospholipid Membrane Binding and Fibril Structure

J Biol Chem. 2016 Sep 30;291(40):21110-21122. doi: 10.1074/jbc.M116.726612. Epub 2016 Aug 16.

Abstract

Human α-synuclein (αS) has been shown to be N terminally acetylated in its physiological state. This modification is proposed to modulate the function and aggregation of αS into amyloid fibrils. Using bacterially expressed acetylated-αS (NTAc-αS) and endogenous αS (Endo-αS) from human erythrocytes, we show that N-terminal acetylation has little impact on αS binding to anionic membranes and thus likely not relevant for regulating membrane affinity. N-terminal acetylation does have an effect on αS aggregation, resulting in a narrower distribution of the aggregation lag times and rates. 2D-IR spectra show that acetylation changes the secondary structure of αS in fibrils. This difference may arise from the slightly higher helical propensity of acetylated-αS in solution leading to a more homogenous fibril population with different fibril structure than non-acetylated αS. We speculate that N-terminal acetylation imposes conformational restraints on N-terminal residues in αS, thus predisposing αS toward specific interactions with other binding partners or alternatively decrease nonspecific interactions.

Keywords: amyloid; circular dichroism (CD); lipid-protein interaction; post-translational modification (PTM); protein conformation; protein self-assembly.

MeSH terms

  • Acetylation
  • Humans
  • Membranes, Artificial*
  • Phospholipids / chemistry*
  • Phospholipids / metabolism
  • Protein Aggregates*
  • Spectrophotometry, Infrared
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism

Substances

  • Membranes, Artificial
  • Phospholipids
  • Protein Aggregates
  • SNCA protein, human
  • alpha-Synuclein